Neuromodulation to restore conscious decision-making during seizures NIH/NINDS R21 Resubmission March 5, 2019 Project Summary Epilepsy, one of the most common neurological disorders, is increasingly recognized as a neural network disorder. Even localized seizures such as the complex partial or focal impaired awareness seizures (CPS) of temporal lobe epilepsy are known to cause neurological deficits in functions outside that of the local onset brain regions. For example, even focal temporal lobe seizures most often induce loss of awareness. Impaired consciousness in epilepsy has numerous adverse outcomes, including motor vehicle accidents, injuries, poor work and school performance and social stigmatization. For the more the one-third of epilepsy patients who are poorly controlled with medications this has a tremendous impact on their quality of life, morbidity and even mortality. Thus, the development of novel therapeutic techniques to prevent seizures and ictal loss of consciousness would provide an important new avenue for treatment. The long-term objectives of the proposed study are to understand the neural network dynamics that underlie the global network changes induced by seizures and establish a novel neuromodulatory technique to treat seizures by restoring consciousness during the ictal and post-ictal periods. This loss of consciousness is marked by the transition of cortical EEG from that of awake cortex to delta slow waves, which are also seen in deep sleep, anesthesia and coma. My collaborator, Dr. Hal Blumenfeld, has developed the network inhibition hypothesis as a mechanism for the ictal loss of consciousness. Working together, we have developed preliminary data that has identified potential targets for neuromodulation to block the effect of seizures and restore ictal and post-ictal awareness. We have preliminary data, both published and unpublished, suggesting that the stimulation of thalamic and brainstem regions of the arousal network can block the typical seizure related behaviors (freezing, automatisms) that are commonly witnessed during ictal and post-ictal states. However, this novel approach has not been tested in awake behaving animals during active decision making. These data are required in order to evaluate the effectiveness of this potentially ground-breaking therapy to restore consciousness during and after seizures. We aim to test our hypothesis by implanting chronic stimulating and recording electrodes to study the neural network changes, consciousness and behavioral deficits during seizures and the post-ictal period and the ability of our neuromodulation therapy to restore active decision making during a behavioral task. In addition, we will evaluate memory function during the ictal and post-ictal states with and without stimulation. The ultimate goal of this research is to lay the foundation for a therapeutic clinical trial based on these findings. Our goal will be to translate these findings through subsequent R01 and NINDS Cooperative Agreement funding in the Translational Research Program in collaboration with industry partners to carry out safety and efficacy testing with a new therapeutic target for our patients with refractory epilepsy.